A cross-sectional survey of plasma viral load among infected sooty mangabeys (SMM) demonstrated levels of active SIV replication (>105 viral RNA copies/ml) that equal, and in some cases exceed, those seen in macaques with advanced SIV-induced immunodeficiency. The observation that naturally SIV-infected SMMs harbored such high plasma viral loads was unexpected and suggested that the immune responses of SMMs do not significantly modify the level of SIV replication. We performed additional SIV PCR assay validation to rigorously demonstrate that the measured levels of SIV were indeed high and not due to assay artifacts. In order to better understand the basis of non-pathogenic SIV infection of SMMs, we have implemented protocols to define the phenotypes, numbers and tissue distribution of cells containing SIV in infected SMMs, and we are performing comparisons of SIV replication in SMMs and rhesus macaques (pathogenic SIV infection). The finding of histologically normal lymphoi d tissues in infected SMMs indicates that the interaction of virus with SMM host cells is not cytopathic.